Abstract A027: Peripheral Immune Dynamics and Biomarkers of Clinical Response in Patients with Castration-Resistant Prostate Cancer Treated with Combination Immunotherapy

Abstract Background: Immune checkpoint blockade (ICB) has minimal clinical activity in unselected patients with castration-resistant prostate cancer (CRPC). The phase I/II Quick Efficacy Seeking Trial (QuEST1, NCT03493945) evaluating the potential of combination immunotherapy in CRPC was designed to generate a tumor-directed immune response with BNVax (a vaccine targeting brachyury, a transcription factor linked to invasion/metastasis) and facilitate the resulting anti-tumor activity with ICB (with bintrafusp alfa (BA), a bifunctional dual inhibitor of PD-L1 and TGF-β) and a lymphocyte stimulating immunocytokine (the IL-15 receptor superagonist nogapendekin alfa inbakicept-pmln (NAI), also known as N-803). A manageable safety profile and promising anti-tumor activity was previously reported with the triplet regimen of BNVax+BA+NAI, eliciting durable PSA responses in 7/24 patients (29%, 6 with pMMR disease), including two confirmed radiographic partial responses, compared to PSA responses in 1/13 patients (8%) with the doublet regimen of BNVax+BA.1,2 Here, we compare peripheral immune dynamics between treatment arms, and evaluate immune biomarkers of clinical response. Methods: Detailed immune profiling included assessment of complete blood counts, PBMC subsets, TCR diversity, RNA expression profiles, and serum analytes in peripheral blood collected at baseline, two, and ten weeks from patients with CRPC receiving the triplet (n=24) and doublet (n=13) therapies. Results: Absolute lymphocyte count (ALC) was increased from baseline to two weeks with the triplet regimen, with an 8-fold greater magnitude of increase observed compared to the doublet. Patients receiving the triplet also had greater increases in total NK cells, refined NK subsets expressing markers of activation/adhesion, ratios of effector to suppressor cells, proinflammatory serum analytes, gene expression profiles reflecting increased NK and T cell activity, and T cell receptor diversity, than patients receiving the doublet. Immune parameters at baseline associated with clinical response to the triplet included higher frequencies of CD4+and CD8+ T cells expressing 41BB and lower frequencies of suppressor cells. A multivariable logistic regression model built with serum analyte levels at baseline efficiently predicted clinical response (accuracy=0.941, p=0.00026). Changes in immune cell subsets and serum analytes that associated with clinical response included greater increases in NKp30+ mature NK cells at two weeks, and serum IFN-g at ten weeks. Conclusions: These findings indicate that the addition of NAI to tumor-targeted vaccine and ICB results in increased clinical activity, enhanced ALC levels, and immune activation of both NK and T cells. These observations warrant further investigation of easily accessible peripheral biomarkers, including ALC, in patients with CRPC and suggest that evaluation of an array of circulating biomarkers may be beneficial in predicting clinical response. Citation Format: Nicole J. Toney, Megan T. Lynch, Stephanie C. Pitts, Jason M. Redman, Patrick Soon-Shiong, James L. Gulley, Jeffrey Schlom, Renee N. Donahue. Peripheral Immune Dynamics and Biomarkers of Clinical Response in Patients with Castration-Resistant Prostate Cancer Treated with Combination Immunotherapy [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A027.